This invention relates generally to novel inhibitors of factor Xa with a neutral P1 specificity group, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.
WO 96/28427 describes benzamidine anticoagulants of the formula: 
wherein Z1 and Z2 are O, N(R), S or OCH2 and the central ring may be phenyl or a variety of heterocycles. The presently claimed compounds do not contain the Z1 linker or the substitution pattern of the above compounds.
WO 95/13155 and PCT International Application US 96/07692 describe isoxazoline and isoxazole fibrinogen receptor antagonists of the formula: 
wherein R1 may be a basic group, Uxe2x80x94V may be a six-membered aromatic ring, Wxe2x80x94X may be a variety of linear or cyclic groups, and Y is an oxy group. Thus, these compounds all contain an acid functionality (i.e., Wxe2x80x94Xxe2x80x94C(xe2x95x90O)xe2x80x94Y). In contrast, the presently claimed compounds do not contain such an acid functionality.
EP 0,513,387 depicts active oxygen inhibitors which are oxazoles or thiazoles of the formula: 
wherein X is O or S, R2 is preferably hydrogen, and both R1 and R3 are substituted cyclic groups, with at least one being phenyl. The presently claimed invention does not relate to these types of oxazoles or thiazoles.
WO 95/18111 addresses fibrinogen receptor antagonists, containing basic and acidic termini, of the formula: 
wherein R1 represents the basic termini, U is an alkylene or heteroatom linker, V may be a heterocycle, and the right hand portion of the molecule represents the acidic termini. The presently claimed compounds do not contain the acidic or basic termini of WO 95/18111.
In U.S. Pat. No. 5,463,071, Himmelsbach et al depict cell aggregation inhibitors which are 5-membered heterocycles of the formula: 
wherein the heterocycle may be aromatic and groups Axe2x80x94Bxe2x80x94Cxe2x80x94 and Fxe2x80x94Exe2x80x94Dxe2x80x94 are attached to the ring system. Axe2x80x94Bxe2x80x94Cxe2x80x94 can be a wide variety of substituents including a basic group attached to an aromatic ring. The Fxe2x80x94Exe2x80x94Dxe2x80x94 group, however, would appear to be an acidic functionality which differs from the present invention. Furthermore, use of these compounds as inhibitors of factor Xa is not discussed.
Baker et al, in U.S. Pat. No. 5,317,103, discuss 5-HT1 agonists which are indole substituted five-membered heteroaromatic compounds of the formula: 
wherein R1 may be pyrrolidine or piperidine and A may be a basic group including amino and amidino. Baker et al, however, do not indicate that A can be a substituted ring system like that contained in the presently claimed heteroaromatics.
Baker et al, in WO 94/02477, discuss 5-HT1 agonists which are imidazoles, triazoles, or tetrazoles of the formula: 
wherein R1 represents a nitrogen containing ring system or a nitrogen substituted cyclobutane, and A may be a basic group including amino and amidino. But, Baker et al do not indicate that A can be a substituted ring system like that contained in the presently claimed heteroaromatics.
Tidwell et al, in J. Med. Chem. 1978, 21(7), 613-623, describe a series of diarylamidine derivatives including 3,5-bis(4-amidinophenyl)isoxazole. This series of compounds was tested against thrombin, trypsin, and pancreatic kallikrein. The presently claimed invention does not include these types of compounds.
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca2+ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.
Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.
Accordingly, one object of the present invention is to provide novel inhibitors of factor Xa with a neutral P1 specificity group or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors discovery that compounds of formula (I): 
or pharmaceutically acceptable salt forms thereof, wherein D, E, M, and R are defined below, are effective factor Xa inhibitors.
[1] Thus, in a first embodiment, the present invention provides novel compounds of formula I: 
or stereoisomers or pharmaceutically acceptable salts thereof,
wherein;
ring D is phenyl or pyridyl:
E is selected from F, Cl, Br, I, OH, C1-3 alkoxy, SH, C1-3 alkyl-S, S(O)R3b, S(O)2R3a, S(O)2NR2R2a, and OCF3;
R is selected from H, F, Cl, Br, I, OR3, SR3, CO2R3, NO2, and CH2OR3;
alternatively, E and R combine to form methylenedioxy or ethylenedioxy;
M is selected from the group: 
J is O or S;
Ja is NH or NR1a;
Z is selected from a bond, C1-4 alkylene, (CH2)rO(CH2)r, (CH2)rNR3(CH2)r, (CH2)rC(O)(CH2)r, (CH2)rC(O)O(CH2)r, (CH2)rOC(O)(CH2)r, (CH2)rC(O)NR3(CH2)r, (CH2)rNR3C(O)(CH2)r, (CH2)rOC(O)O(CH2)r, (CH2)rOC(O)NR3(CH2)r, (CH2)rNR3C(O)O(CH2)r, (CH2)rNR3C(O)NR3(CH2)r, (CH2)rS(O)p(CH2)r, (CH2)rSO2NR3(CH2)r, (CH2)rNR3SO2(CH2)r, and (CH2)rNR3SO2NR3(CH2)r, provided that Z does not form a Nxe2x80x94N, Nxe2x80x94O, Nxe2x80x94S, NCH2N, NCH2O, or NCH2S bond with ring M or group A;
R1a and R1b are independently absent or selected from xe2x80x94(CH2)rxe2x80x94R1xe2x80x2, xe2x80x94CHxe2x95x90CHxe2x80x94R1xe2x80x2, NCH2R1xe2x80x3, OCH2R1xe2x80x3, SCH2R1xe2x80x3, NH(CH2)2(CH2)tR1xe2x80x2, O(CH2)2(CH2)tR1xe2x80x2, and S(CH2)2(CH2)tR1xe2x80x2;
alternatively, R1a and R1b, when attached to adjacent carbon atoms, together with the atoms to which they are attached form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4 and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S;
alternatively, when Z is C(O)NH and R1a is attached to a ring carbon adjacent to Z, then R1a is a C(O) which replaces the amide hydrogen of Z to form a cyclic imide;
R1xe2x80x2 is selected from H, C1-3 alkyl, F, Cl, Br, I, xe2x80x94CN, xe2x80x94CHO, (CF2)rCF3, (CH2)rOR2, NR2R2a, C(O)R2c, OC(O)R2, (CF2)rCO2R2c, S(O)pR2b, NR2(CH2)rOR2, CH(xe2x95x90NR2c)NR2R2a, NR2C(O)R2b, NR2C(O)NHR2b, NR2C(O)2R2a, OC(O)NR2aR2b, C(O)NR2R2a, C(O)NR2(CH2)rOR2, SO2NR2R2a, NR2SO2R2b, C3-6 carbocyclic residue substituted with 0-2 R4, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
R1xe2x80x3 is selected from H, CH(CH2OR2)2, C(O)R2c, C(O)NR2R2a, S(O))R2b, S(O)2R2b, and SO2NR2R2a;
R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, phenethyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b; p2 R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4band containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3a, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3b, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
R3c, at each occurrence, is selected from C1-4 alkyl, and phenyl;
A is selected from:
C3-10 carbocyclic residue substituted with 0-2 R4, and
5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
B is selected from: H, Y, and Xxe2x80x94Y;
X is selected from C1-4 alkylene, xe2x80x94CR2(CR2R2b)(CH2)txe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(xe2x95x90NR1xe2x80x2)xe2x80x94, xe2x80x94CR2(NR1xe2x80x3R2)xe2x80x94, xe2x80x94CR2(OR2)xe2x80x94, xe2x80x94CR2(SR2)xe2x80x94, xe2x80x94C(O)CR2R2a, xe2x80x94CR2R2aC(O), xe2x80x94S(O)pxe2x80x94, xe2x80x94S(O)pCR2R2axe2x80x94, xe2x80x94CR2R2aS(O)pxe2x80x94, xe2x80x94S(O)2NR2xe2x80x94, xe2x80x94NR2S(O)2xe2x80x94, xe2x80x94NR2S(O)2CR2R2axe2x80x94, xe2x80x94CR2R2aS(O)2NR2xe2x80x94, xe2x80x94NR2S(O)2NR2xe2x80x94, xe2x80x94C(O)NR2xe2x80x94, xe2x80x94NR2C(O)xe2x80x94, xe2x80x94C(O)NR2CR2R2axe2x80x94, xe2x80x94NR2C(O)CR2R2axe2x80x94, xe2x80x94CR2R2aC(O)NR2xe2x80x94, xe2x80x94CR2R2aNR2C(O)xe2x80x94, xe2x80x94NR2C(O)Oxe2x80x94, xe2x80x94OC(O)NR2xe2x80x94, xe2x80x94NR2C(O)NR2xe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94NR2CR2R2axe2x80x94, xe2x80x94CR2R2aNR2xe2x80x94, O, xe2x80x94CR2R2aOxe2x80x94, and xe2x80x94OCR2R2axe2x80x94;
Y is selected from:
(CH2)rNR2R2a, provided that Xxe2x80x94Y do not form a Nxe2x80x94N, Oxe2x80x94N, or Sxe2x80x94N bond,
C3-10 carbocyclic residue substituted with 0-2 R4a, and
5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4a;
R4, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, NR2C(O)NR2R2a, CH(xe2x95x90NR2)NR2R2a, CH(xe2x95x90NS(O)2R5)NR2R2a, NHC(xe2x95x90NR2)NR2R2a, C(O)NHC(xe2x95x90NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, NR2SO2R5, S(O)pR5, (CF2)rCF3, NCH2R1xe2x80x3, OCH2R1xe2x80x3, SCH2R1xe2x80x3, N(CH2)2(CH2)tR1xe2x80x2, O(CH2)2(CH2)tR1xe2x80x2, and S(CH2)2(CH2)tR1xe2x80x2,
alternatively, one R4 is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
provided that if B is H, then R4 is other than tetrazole, C(O)-alkoxy, and C(O)NR2R2a;
R4a, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, (CH2)rxe2x80x94F, (CH2)rxe2x80x94Br, (CH2)rxe2x80x94Cl, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR2R2a, (CH2)rNR2R2b, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, C(O)NH(CH2)2NR2R2a, NR2C(O)NR2R2a, CH(xe2x95x90NR2)NR2R2a, NHC(xe2x95x90NR2)NR2R2a, SO2NR2R2a, NR2SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, C(O)NHSO2xe2x80x94C1-4 alkyl, NR2SO2R5, S(O)pR5, and (CF2)rCF3;
alternatively, one R4a is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-1 R5;
R4b, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR3, F, Cl, Br, I, C1-4 alkyl, xe2x80x94CN, NO2, (CH2)rNR3R3a, (CH2)rC(O)R3, (CH2)rC(O)OR3c, NR3C(O)R3a, C(O)NR3R3a, NR3C(O)NR3R3a, CH(xe2x95x90NR3)NR3R3a, NH3C(xe2x95x90NR3)NR3R3a, SO2NR3R3a, NR3SO2NR3R3a, NR3SO2xe2x80x94C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)pCF3, S(O)pxe2x80x94C1-4 alkyl, S(O)p-phenyl, and (CF2)rCF3;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl substituted with 0-2 R6, and benzyl substituted with 0-2 R6;
R6, at each occurrence, is selected from H, OH, (CH2)rOR2, F, Cl, Br, I, C1-4 alkyl, CN, NO2, (CH2)rNR2R2a, (CH2)rC(O)R2b, NR2C(O)R2b, NR2C(O)NR2R2a, CH(xe2x95x90NH)NH2, NHC(xe2x95x90NH)NH2, SO2NR2R2a, NR2SO2NR2R2a, and NR2SO2C1-4 alkyl;
n is selected from 0, 1, 2, and 3;
m is selected from 0, 1, and 2;
p is selected from 0, 1, and 2;
r is selected from 0, 1, 2, and 3;
s is selected from 0, 1, and 2; and,
t is selected from 0 and 1.
[2] In a preferred embodiment, the present invention provides novel compounds, wherein M is selected from the group: 
Z is selected from (CH2)rC(O)(CH2)r, (CH2)rC(O)O(CH2)r, (CH2)rC(O)NR3(CH2)r, (CH2)rS(O)p(CH2)r, and (CH2)rSO2NR3(CH2)r; and,
Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole;
Y may also be selected from the following bicyclic heteroaryl ring systems: 
K is selected from O, S, NH, and N.
[3] In a more preferred embodiment, the present invention provides novel compounds of formula Ia or Ib: 
wherein;
ring D is phenyl or pyridyl:
E is selected from F, Cl, Br, and C1-3 alkoxy;
R is selected from H, F, Cl, Br, OR3, and CH2OR3;
M is selected from the group: 
Z is selected from (CH2)rC(O)(CH2)rand (CH2)rC(O)NR3(CH2)r; and,
Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, benzofuran, benzothiofuran, indole, benzimidazole, benzoxazole, benzthiazole, indazole, benzisoxazole, benzisothiazole, and isoindazole.
[4] In an even more preferred embodiment, the present invention provides novel compounds of formula Ia, wherein;
ring D is phenyl;
E is selected from F, Cl, Br, and OCH3;
R is selected from H, F, Cl, and Br;
M is selected from the group: 
A is selected from:
C5-6 carbocyclic residue substituted with 0-2 R4, and
5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R4a;
phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, benzimidazolyl, oxadiazole, thiadiazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, and 1,3,4-triazole;
R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C5-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, phenethyl, C5-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, benzyl, C5-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
R2c, at each occurrence, is selected from CF3, OH, C1-4 alkoxy, C1-6 alkyl, benzyl, C5-6 carbocyclic residue substituted with 0-2 R4b, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4b;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a ring selected from imidazolyl, morpholino, piperazinyl, pyridyl, and pyrrolidinyl, substituted with 0-2 R4b;
R4, at each occurrence, is selected from H, xe2x95x90O, OR2, CH2OR2, F, Cl, C1-4 alkyl, NR2R2a, CH2NR2R2a, C(O)R2c, CH2C(O)R2c, C(O)NR2R2a, CH(xe2x95x90NR2)NR2R2a, CH(xe2x95x90NS(O)2R5)NR2R2a, SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, S(O)2R5, and CF3 
provided that if B is H, then R4 is other than tetrazole, C(O)-alkoxy, and C(O)NR2R2a;
R4a, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR2, F, Cl, C1-4 alkyl, NR2R2a, CH2NR2R2a, NR2R2b, CH2NR2R2b, (CH2)rC(O)R2c, NR2C(O)R2b, C(O)NR2R2a, C(O)NH(CH2)2NR2R2a, NR2C(O)NR2R2a, SO2NR2R2a, S(O)2R5, and CF3; and,
R4b, at each occurrence, is selected from H, xe2x95x90O, (CH2)rOR3, F, Cl, C1-4 alkyl, NR3R3a, CH2NR3R3a, C(O)R3, CH2C(O)R3, C(O)OR3c, C(O)NR3R3a, CH(xe2x95x90NR3)NR3R3a, SO2NR3R3a, NR3SO2xe2x80x94C1-4 alkyl, NR3SO2CF3, NR3SO2-phenyl, S(O)2CF3, S(O)2xe2x80x94C1-4 alkyl, S(O)2-phenyl, and CF3.
[5] In a further even more preferred embodiment, the present invention provides novel compounds selected from:
3-Methyl-1-phenyl-1H-pyrazole-5-(N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Methyl-1-(2-methoxy)phenyl-1H-pyrazole-5-(N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
3-Methyl-1-(3-methoxy)phenyl-1H-pyrazole-5-(N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
3-Methyl-1-(4-methoxy)phenyl-1H-pyrazole-5-(N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
3-Methyl-1-(2-hydroxy)phenyl-1H-pyrazole-5-(N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
3-Methyl-1-(3-hydroxy)phenyl-1H-pyrazole-5-(N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
3-Methyl-1-(4-hydroxy)phenyl-1H-pyrazole-5-(N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
3-Methyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
3-Methyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(3-bromo-4-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
3-Methyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(3-iodo-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
3-Methyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(3-methyl-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
3-Methyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(4-N-carboxyldimethylamine)phenyl)carboxyamide;
3-Methyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(4-N-pyrrolidinocarbonyl)phenyl)carboxyamide;
3-Methyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(4-a-methyl-N-pyrrolidino)phenyl)carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(4-N-pyrrolidinocarbonyl)phenyl)carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(5-(2-methanesulfonyl)phenyl)pyridin-2-yl)carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(5-N-pyrrolidinocarbonyl)pyridin-2-yl)carboxyamide;
3-Methyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(5-N-pyrrolidinocarbonyl)pyridin-2-yl)carboxyamide;
3-Methyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(5-(2-sulfonamido)phenyl)pyridin-2-yl)carboxyamide;
3-Methyl-1-(4-methoxyphenyl)-1H-pyrazole-5-N-(4-(N-carboxyl-3-hydroxypyrrolidino)phenyl)carboxyamide;
2-Amino-4-(4-methoxyphenyl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
2-Bromo-4-(4-methoxyphenyl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
2-Chloro-4-(4-methoxyphenyl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
2-Chloro-4-(4-phenoxy)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
2-Methoxy-4-(4-methoxyphenyl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
2-Thiomethyl-4-(4-methoxyphenyl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
2-Methylsulfoxide-4-(4-methoxyphenyl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
2-Methylsulfone-4-(4-methoxyphenyl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
2-Cyano-4-(4-methoxyphenyl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
2-N,N-Dimethylamino-4-(4-methoxyphenyl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
2-(1-Pyrrole)-4-(4-methoxyphenyl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
3-(4-Methoxyphenyl)-5-[5-(2xe2x80x2-aminosulfonylphenyl-1-yl)pyridin-2-yl]aminocarbonyl-5-carbomethoxymethyl-isoxazoline;
3-(4-Methoxyphenyl)-5-[5-(2xe2x80x2-aminosulfonylphenyl-1-yl)pyridin-2-yl]aminocarbonyl-5-carboxymethyl-isoxazoline;
3-(4-Methoxyphenyl)-5-[5-(2xe2x80x2-aminosulfonylphenyl-1-yl)pyridin-2-yl]aminocarbonyl-5-(N-carbomethoxymethyl)carboxamidomethyl-isoxazoline;
3-(4-Methoxyphenyl)-5-[5-(2xe2x80x2-aminosulfonylphenyl-1-yl)pyridin-2-yl]aminocarbonyl-5-(1,2,4-triazol-1-yl)methyl-isoxazoline;
1-(4-Methoxyphenyl)-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]tetrazole;
3-Methyl-1-(4-methoxy-3-chloro)phenyl-1H-pyrazole-5-(N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
3-Methyl-1-(4-trifluoromethoxy)phenyl-1H-pyrazole-5-(N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-(3-Bromophenyl)-3-methyl-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-(3-Iodophenyl)-3-methyl-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-(3,4-Methylenedioxanephenyl)-3-methyl-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-(4-Methoxyphenyl)-3-hydroxylmethylene-1H-pyrazole-5-(4xe2x80x2-pyrrolidinocarbonyl)anilide;
1-(4-Methoxyphenyl)-3-formaldehyde-1H-pyrazole-5-(4xe2x80x2-pyrrolidinocarbonyl)anilide;
1-(4-Methoxyphenyl)-5-(4xe2x80x2-pyrrolidinocarbonyl)anilide-3-pyrazolecarboxylic acid;
1-(4-Methoxyphenyl)-3-methylcarboxylate-1H-pyrazole-5-(4xe2x80x2-pyrrolidinocarbonyl)anilide;
1-(4xe2x80x2-Chlorophenyl)-3-methyl-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-(4xe2x80x2-Chlorophenyl)-3-methyl-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1-pyridyl-1xe2x80x2-phenyl]-4-yl)carboxyamide;
1-(3xe2x80x2,4xe2x80x2-Dichlorophenyl)-3-methyl-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-(3xe2x80x2-Chlorophenyl)-3-methyl-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
2-Amino-4-phenyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
2-Chloro-4-phenyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
2-Amino-4-[3-(bromo)-4-(fluoro)-phenyl]-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
2-Amino-4-[4-fluorophenyl]-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
2-Amino-4-[3-bromophenyl]-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
2-Chloro-4-[3-bromophenyl]-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
N-(2xe2x80x2-Aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)-1-(4-methoxyphenyl)-3-(methylthio)pyrazole-5-carboxamide;
1-(4-Methoxyphenyl)-3-(methylsulfonyl)-N-(5-(2xe2x80x2-methylsulfonylphenyl)pyrimid-2-yl)pyrazole-5-carboxamide;
N-(2xe2x80x2-Aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-pyrazole-5-carboxamide;
N-(4-Benzoylpyrrolidino)-1-(4-methoxyphenyl)-3-(methylthio)-1H-pyrazole-5-carboxamide;
1-(4-Methoxyphenyl)-N-(5-(2xe2x80x2-methylsulfonylphenyl)pyrimid-2-yl)-3-(methylthio)-1H-pyrazole-5-carboxamide;
N-(4-Benzoylpyrrolidino)-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-pyrazole-5-carboxamide;
N-(2xe2x80x2-Aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)-1-(4-methoxyphenyl)-3-(methoxymethyl)-1H-pyrazole-5-carboxamide;
N-(2xe2x80x2-Aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)-1-(4-methoxyphenyl)-3-carbomethoxy-1H-pyrazole-5-carboxamide;
N-(2xe2x80x2-Aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)-1-(4-methoxyphenyl)-3-(methylsulfonylmethyl)-1H-pyrazole-5-carboxamide;
3-Trifluoromethyl-l-(4-methoxyphenyl)-1H-pyrazole-5-(N-(5-(2-methanesulfonyl)phenyl)pyrimidin-2-yl)carboxyamide;
3-Methyl-1-(4-methoxyphenyl)-1H-pyrazole-5-N-(4-(N-carboxyl-2-carbomethoxypyrrolidino)phenyl)carboxyamide;
3-Methyl-1-(4-methoxyphenyl)-1H-pyrazole-5-N-(4-(N-carboxyl-3-aminopyrrolidino)phenyl)carboxyamide;
3-Methyl-1-(4-methoxyphenyl)-1H-pyrazole-5-N-(4-(N-carboxyl-3-methoxypyrrolidino)phenyl)carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(5-(2-aminosulfonyl)phenyl)pyridin-2-yl)carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(4-amidino)phenyl)carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(N-pyrrolidino)formylimino)phenyl)carboxyamide;
3-Trifluoromethyl-5-(N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl))-1-(4-methoxyphenyl)pyrrolo[3,4-d]pyrazole-4,6-(1H,5H)-dione;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-carbomethoxy-(N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-hydoxymethyl-(N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl))carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-2-fluoro(4-(N-pyrrolidino)formylimino)phenyl)carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(N-pyrrolidino)formyl-N-((2-propyl)methylcarbamoyl)imino)phenyl)carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(N-pyrrolidino)formyl-N-(methanesulfamoyl)imino)phenyl)carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-((4-amidino)phenyl)methyl)carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-((4-(N-pyrrolidino)formylimino)phenyl)methyl)carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-((1-benzyl)piperidin-4-yl)carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-((1-(pyridin-2-yl)methyl)piperidin-4-yl)carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(2-methylimidazo-1-yl))phenyl)carboxyamide;
3-Methyl-(4-methoxy)phenyl-1H-pyrazole-5-(N-{4-(5-methyl-imidazol-1-yl}phenyl)carboxyamide;
3-Methyl-(4-methoxy)phenyl-1H-pyrazole-5-(N-{4-(4-methyl-imidazol-1-yl}phenyl)carboxyamide,;
3-Trifluoromethyl-(4-methoxy)phenyl-1H-pyrazole-5-(N-{4-(5-carbomethoxy-imidazol-1-yl}phenyl)carboxyamide;
3-Trifluoromethyl-(4-methoxy)phenyl-1H-pyrazole-5-(N-{4-(5-carboxy-imidazol-1-yl}phenyl)carboxyamide;
1-(4xe2x80x2-Methoxyphenyl)-3-hydroxylmethyl-1H-pyrazole-5-N-(4xe2x80x2-pyrrolidinocarbonyl)phenyl)carboxyamide;
1-(4xe2x80x2-Methoxyphenyl)-3-formaldehyde-1H-pyrazole-5-N-(4xe2x80x2-(pyrrolidinocarbonyl)phenyl)carboxyamide;
1-(4xe2x80x2-Methoxyphenyl)-5-N-(4xe2x80x2-(pyrrolidinocarbonyl)anilide)-1H-pyrazol-3-yl-carboxylic acid;
1-(4xe2x80x2-Methoxyphenyl)-3-methylcarboxylate-1H-pyrazole-5-N-(4xe2x80x2-pyrrolidinocarbonyl)phenyl)carboxyamide;
1-(4xe2x80x2-Methoxyphenyl)-3-cyanomethyl-1H-pyrazole-5-N-(4xe2x80x2-pyrrolidinocarbonyl)phenyl)carboxyamide;
2-(1xe2x80x2-(4xe2x80x3-Methoxyphenyl)-5xe2x80x2-(4xe2x80x3-pyrrolidinyl-one)anilide-1H-pyrazol-3xe2x80x2-yl)acetic acid;
1-(4xe2x80x2-Methoxyphenyl)-3-bromomethyl-1H-pyrazole-5-N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-(4xe2x80x2-Methoxyphenyl)-3-aminomethyl-1H-pyrazole-5-N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-(4xe2x80x2-Methoxyphenyl)-3-(N-methylsulfonylamino)methyl-1H-pyrazole-5-N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-(4xe2x80x2-Methoxyphenyl)-3-(imidazol-1-yl)methyl-1H-pyrazole-5-N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-(4xe2x80x2-Methoxyphenyl)-3-hydroxylmethyl-1H-pyrazole-5-N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-(4xe2x80x2-Methoxyphenyl)-3-trifluoroacetylhydroxylmethyl-1H-pyrazole-5-N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-(4xe2x80x2-Methoxy-2xe2x80x2-methoxycarbonylphenyl)-3-trifluoromethyl-1H-pyrazole-5-N-(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-(4xe2x80x2-Methoxy-2xe2x80x2-hydroxycarbonylphenyl)-3-trifluoromethyl-1H-pyrazole-5-N-(2xe2x80x2-methylsulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-(4xe2x80x2-Methoxy-2xe2x80x2-methoxycarbonylphenyl)-3-trifluoromethyl-1H-pyrazole-5-N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-(4xe2x80x2-Methoxy-2xe2x80x2-hydroxycarbonylphenyl)-3-trifluoromethyl-1H-pyrazole-5-N-(2xe2x80x2-tert-butylaminosulfonyl-[1,1xe2x80x2]-biphenyl)carboxyamide;
1-(4xe2x80x2-Methoxy-2xe2x80x2-hydroxycarbonylphenyl)-3-trifluoromethyl-1H-pyrazole-5-N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-(4xe2x80x2-Methoxy-2xe2x80x2-hydroxylmethylphenyl)-3-trifluoromethyl-1H-pyrazole-5-N-(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-(4xe2x80x2-Methoxyphenyl)-3-methyl-1H-pyrazole-5-N-(4xe2x80x2-sec-butyl)phenyl)carboxyamide;
1-(4xe2x80x2-Methoxyphenyl)-3-methyl-1H-pyrazole-5-N-(4xe2x80x2-(3xe2x80x3-methyl-3xe2x80x3]-pyrazolin-5xe2x80x3-one-2xe2x80x3-yl)phenyl)carboxyamide;
1-(4xe2x80x2-Methoxyphenyl)-3-methyl-1H-pyrazole-5-N-(4t-(6xe2x80x3-methylbenzothiazol-2xe2x80x3-yl)phenyl)carboxyamide;
1-(4xe2x80x2-Methoxyphenyl)-3-methyl-1H-pyrazole-5-N-(3xe2x80x2,4xe2x80x2-dibromophenyl)carboxyamide;
1-(4xe2x80x2-Methoxyphenyl)-3-methyl-1H-pyrazole-5-N-(4xe2x80x2-n-butyl)phenyl)carboxyamide;
1-(4xe2x80x2-Methoxyphenyl)-3-methyl-1H-pyrazole-5-N-(4xe2x80x2-(4xe2x80x3-methylpiperidino)phenyl)carboxyamide;
1-(4xe2x80x2-Methoxyphenyl)-3-methyl-1H-pyrazole-5-N-(4xe2x80x2-(2xe2x80x3-methylimidazol-1xe2x80x3-yl)phenyl)carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(4-carboxy(N-methylimidazo-2-yl)phenyl)carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(4-hydroxymethyl(2-(imidazol-2-yl)phenyl)))carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(4-hydroxymethyl(2-(1-benzyl-imidazol-2-yl)phenyl)))carboxyamide;
1-(4-Methoxyphenyl)-3-trifluoromethyl-1H-pyrazole-5-(N-(4-(2-carboxy(imidazol-2-yl)phenyl)))carboxyamide;
3-Trifluoromethyl-1-(4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(N-(4-methoxyphenyl)amino-(2-thiazolyl)methyl)phenyl)))carboxyamide;
1-(4-Methoxyphenyl)-3-trifluoromethyl-1H-pyrazole-5-(N-(4-(2-carboxy-(4,5-dihyrothiazol-2-yl)phenyl)))carboxyamide;
1-(4-Methoxyphenyl)-3-trifluoromethyl-1H-pyrazole-5-N-4-(2-(4xe2x80x2,5xe2x80x2-dihydro-1xe2x80x2H-imidazol-2xe2x80x2yl)phenyl)carboxyamide;
1-(4-Methoxyphenyl)-3-trifluoromethyl-1H-pyrazole-5-N-(4-(N-2xe2x80x2-aminoethylenecarboxyamide)phenyl)carboxyamide;
1-(4-Methoxyphenyl)-3-trifluoromethyl-1H-pyrazole-5-[4-(1,4,5,6-tetrahydro-pyrimid-2-yl)-phenyl]carboxyamide;
1-(4-Methoxyphenyl)-3-trifluoromethyl-1H-pyrazole-5-[4-(N-methyl-4,5,6-trihydro-pyrimid-2-yl)-phenyl]carboxyamide;
1-(4-Methoxyphenyl)-3-trifluoromethyl-1H-pyrazole-5-N-1-(2-fluoro-4-imadazolinephenyl)carboxyamide;
1-(4-Methoxyphenyl)-3-trifluoromethyl-1H-pyrazole-5-N-1-(2-fluoro-4-N-methylimadazolinephenyl)carboxyamide;
1-(4-Methoxyphenyl)-3-trifluoromethyl-1H-pyrazole-5-N-[4-(4,5-dihydro-1-N-methyl-imidazo-2-yl)phenyl]carboxyamide;
1-(4-Methoxyphenyl)-3-trifluoromethyl-1H-pyrazole-5-N-[4-carbonylguanidine)phenyl]carboxyamide;
1-(4-Methoxyphenyl)-3-trifluoromethyl-1H-pyrazole-5-N-[4-(pyrimidin-2-yl)phenyl]carboxyamide;
2-(Carboxyamide)-4-[(4-methoxy)phenyl]-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide]thiazole;
2-(2-Methoxyethylamino)-4-[(4-methoxy)phenyl]-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide]thiazole;
2-(3-Hydroxypropylamino)-4-[(4-methoxy)phenyl]-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide]thiazole;
2-(2-Cyanoethylamino)-4-[(4-methoxy)phenyl]-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide]thiazole;
2-(3-Methoxypropylamino)-4-[(4-methoxy)phenyl]-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide]thiazole;
2-(N-b-Alanyl)-4-[(4-methoxy)phenyl]-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide]thiazole;
2-(Isopropylamino)-4-[(4-methoxy)phenyl]-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide]thiazole;
2-(1,3-Dihydroxy-2-propylamino)-4-[(4-methoxy)phenyl]-5-[(2xe2x80x2-aminosulfonyl-[1,1]-biphen-4-yl)carboxyamide]thiazole;
2-[(Methoxycarbonyl)methylamino]-4-[(4-methoxy)phenyl]-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide]thiazole;
2-(N-Glycyl)-4-[(4-methoxy)phenyl]-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide]thiazole;
1-[(4-Methoxy)phenyl]-3-(ethoxycarbonyl)-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl)phenyl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-(carboxyamide)-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl)phenyl)carboxyamide;
1-[(4-Methoxy)phenyl-3-[(2-hydroxyethyl)carboxyamide]-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl)phenyl)carboxyamide;
1-[(4-Methoxy)phenyl)-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl)phenyl)carboxyamide-3-hydroxamic acid;
1-[(4-Methoxy)phenyl]-3-[phenylcarboxyamide]-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl)phenyl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-[(3-hydroxypropyl)carboxyamide]-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl)phenyl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-[methylcarboxyamide]-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl)phenyl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-[(benzyl)carboxyamide]-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl)phenyl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-[(dimethyl)carboxyamide]-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl)phenyl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-[(phenylethyl)carboxyamide]-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl)phenyl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-[(2-hydroxyphenyl)carboxyamide]-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl)phenyl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-[(3-hydroxyphenyl)carboxyamide]-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl)phenyl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-[(4-hydroxyphenyl)carboxyamide]-1H-pyrazole-5-[(4-(N-pyrrolidinocarbonyl)phenyl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-[(methoxycarbonyl)amino]-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-amino-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-[(methoxycarbonyl)methylamino]-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-[(2-hydroxy)ethylamino]-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-[E-2-(methoxycarbonyl)ethenyl]-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-[2-(methoxycarbonyl)ethyl]-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-[E-2-(carboxy)ethenyl-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-[2-(carboxy)ethyl]-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-[E-2-(carboxyamide)ethenyl]-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-[E-2-(hydroxymethyl)ethenyl]-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-(3-hydroxypropyl)-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-propyl-1H-pyrazole-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-(trifluoromethyl)-4-cyano-1H-pyrazole-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-(trifluoromethyl)-4-(amidino)-1H-pyrazole-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-[(4-Methoxy)phenyl)-3-(trifluoromethyl)-4-(N-hydroxyamidino)-1H-pyrazole-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
1-[(4-Methoxy)phenyl]-3-(trifluoromethyl)-4-(ethoxycarbonyl)-1H-pyrazole-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)carboxyamide; and,
1-[(4-Methoxy)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-[(2xe2x80x2-methylsulfonyl-3-fluoro-[1,1xe2x80x2]-biphen-4-yl)carboxyamide-4-carboxylic acid;
and pharmaceutically acceptable salts thereof.
[6] In a second embodiment, the present invention provides novel compounds of formula II: 
or stereoisomers or pharmaceutically acceptable salts thereof, wherein;
M is selected from the group: 
is selected from C(O)CH2 and C(O)NR3;
R1a is xe2x80x94(CH2)rxe2x80x94R1;
R1xe2x80x2 is selected from H, C1-3 alkyl, F, Cl, Br, CH(CH2OR2)2, (CF2)rCF3, (CH2)rOR2, NR2R2a, S(O)pR2b, NR2(CH2)rOR2, NR2C(O)R2b, C(O)NR2R2a, C(O)NR2(CH2)rOR2, and SO2NR2R2a;
R2, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
R2a, at each occurrence, is selected from H, CF3, C1-6 alkyl, benzyl, C3-6 carbocyclic residue substituted with 0-2 R4, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
R2b, at each occurrence, is selected from CF3, C1-4 alkoxy, C1-6 alkyl, C3-6 carbocyclic residue substituted with 0-2 R4, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R4;
alternatively, R2 and R2a, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R4 which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R3, at each occurrence, is selected from H, C1-4 alkyl, and phenyl;
A is selected from phenyl, pyridyl, and pyrimidyl, and A is substituted with 0-2 R4;
B is selected from: H and Y;
Y is selected from phenyl, pyridyl, tetrazolyl, and morpholino, and Y is substituted with 0-2 R4a;
R4, at each occurrence, is selected from F, Cl, Br, I, C(O)NR2R2a, and (CF2)rCF3;
R4a, at each occurrence, is selected from F, Cl, Br, I, C1-4 alkyl, C(O)NR2R2a, SO2NR2R2a, NR2SO2xe2x80x94C1-4 alkyl, S(O)pR5, and (CF2)rCF3;
R5, at each occurrence, is selected from CF3, C1-6 alkyl, phenyl, and benzyl;
p is selected from 0, 1, and 2; and,
r is selected from 0, 1, 2, and 3.
[7] In another more preferred embodiment, the present invention provides novel compounds selected from:
3-Methyl-1-phenyl-1H-pyrazole-5-(N-(2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)carboxyamide;
2-Amino-4-phenyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole; and,
2-Chloro-4-phenyl-5-[(2xe2x80x2-aminosulfonyl-[1,1xe2x80x2]-biphen-4-yl)aminocarbonyl]thiazole;
and pharmaceutically acceptable salts thereof.
In a third embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
In a fourth embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., R6) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R6, then said group may optionally be substituted with up to two R6 groups and R6 at each occurrence is selected independently from the definition of R6. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9cC1-6 alkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl; xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and, amine functional groups in the compounds of formula (I), and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of Formula I can be prepared using the reactions and techniques described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).
Preparation of Compounds of Formula I with a Five-membered Heterocyclic Core
General syntheses for compounds of Formula I are outlined in Schemes 1a-b, The M ring may be N-linked or C-linked to the ring referred to in the following scheme as ring D. Bxe2x80x2 and Rf are protected functional groups that can be converted to R, B and R1arespectively. It is understood that group E may or may not be protected or a precursor to E of Formula I, depending upon the demands of the chemistry involved. The compounds can also be obtained by changing the sequences of the reaction steps as described in Scheme 1. For N-linked M ring, the appropriate amine-substituted ring D is treated under conditions described in xe2x80x9cThe Chemistry of Heterocyclic Compounds, Weissberger, A. and Taylor, E. C. Ed., John Wiley and Sonsxe2x80x9d or as described later in the synthesis section to give N-linked ring M. Further modifications and deprotections give N-linked ring M with R, Zxe2x80x94Axe2x80x94B and R1a substitutents. 
For C-linked five-membered ring M, the above aniline is diazotized with nitrous acid and treated with NaBr to give the heterocyclic bromide. Treatment with n-BuLi followed by DMF gives aldehyde which can be converted to ring M as described in xe2x80x9cThe Chemistry of Heterocyclic Compounds, Weissberger, A. and Taylor, E. C. Ed., John Wiley and Sonsxe2x80x9d or as described later in the synthesis section. Other precursor functional groups like acid, cyanide, methylketone, etc. can also be used to form the ring M. Further modifications and deprotections can yield five-membered ring M substituted with R, Zxe2x80x94Axe2x80x94B and R1a. The corresponding C-linked six-membered ring M can be obtained by converting the above bromide with n-butyl lithium and triisopropyl borate to give the heterocylic boronic acid. Suzuki coupling with the appropriate heterocyclic bromide, followed by modifications and deprotections gives the C-linked six-membered ring M with R, Zxe2x80x94Axe2x80x94B and R1a substitutents. 
The compounds of the present invention in which the M-heterocycle is thiazole can be prepared according to the procedures described in Scheme 2. The appropriate ring D bromide can be converted into a beta-keto ester in several ways. One preferred method involves transmetallation with an alkyllithium reagent followed by quenching with DMF to afford the corresponding aldehyde. Addition of ethyl diazoacetate in the presence of tin (II) chloride affords the beta-ketoester directly. Other methods are available for this conversion, one of which involves Reformatsky reaction of the aldehyde followed by oxidation to the beta-keto ester. 
A second preferred method for converting the bromide into a beta-keto ester involves palladium catalysed coupling with (ethoxyvinyl)tributyltin followed by acidic hydrolysis to afford the corresponding acetyl derivative. Many methods exist for conversion of the acetyl derivative to the beta-ketoester, one preferred method of which involves reacting the acetyl derivative with a dialkyl carbonate in the presence of a base such as sodium hydride or lithium diisopropylamide. The beta-ketoester can be converted into the corresponding thiazole derivatives by bromination with NBS followed by cyclization with an appropriate thiourea or thioamide in a solvent such as ethanol or tetrahydrofuran. A one pot method for this conversion involves treating the beta-ketoester with hydroxytosyloxyiodobenzene in acetonitrile, which forms an intermediate alpha-tosyloxy-beta-ketoester, followed by addition of a thiourea or thioamide to effect cyclization to the corresponding thiazole. Manipulation of the ester group of these thiazoles can then afford the compounds containing an appropriate Zxe2x80x94Axe2x80x94B group. Where Zxe2x95x90CONH, standard methods of peptide coupling with an appropriate amine can be employed, such as reaction of the ester with an aluminum reagent derived from the amine. Where Zxe2x95x90COCH2, formation of the acid chloride by standard methods can be followed by addition of an appropriate zinc reagent. The R1a group on the thiazole ring can also be manipulated to provide a variety of different groups. For example, when thiourea is used as the cyclization partner, a 2-aminothiazole is produced. This amino group can be readily diazotized and displaced with the appropriate copper halide to afford 2-halothiazoles. The halogen atom can then be readily displaced by a variety of carbon, nitrogen, oxygen and sulfur nucleophiles to produce a wide variety of alkyl, aryl, heteroatom, and heterocyclic derivatives of R1a.
The tetrazole compounds of this invention where Z is xe2x80x94CONHxe2x80x94 can be prepared as exemplified in Scheme 3. An appropiately substituted amine (Exe2x80x94Dxe2x80x94NH2) is acylated with ethyl oxalyl chloride. The resulting amide can be converted to the tetrazole either by the methods described by Duncia (J. Org. Chem. 1991, 2395-2400) or Thomas (Synthesis 1993, 767-768, 1993). The amide can be converted to the iminoyl chloride first and the reacted with NaN3 to form the 5-carboethoxytetrazole (J. Org. Chem. 1993, 58, 32-35 and Bioorg. and Med. Chem. Lett. 1996, 6, 1015-1020). The 5-carboethoxytetrazole is then coupled with an appropriate amine (BANH2) by the method described by Weinreb (Tetr. Lett. 1977, 48, 4171-4174). Final deprotection as described before yields the desire product.
The tetrazole compounds of this invention where Z is xe2x80x94COxe2x80x94 can also be prepared via iminoyl chloride (Chem. Ber. 1961, 94, 1116 and J. Org. Chem. 1976, 41, 1073) using an appropriately substituted acyl chloride as starting material. The ketone-linker can be reduced to compounds where Z is alkyl. 
The tetrazole compounds of this invention where Z is xe2x80x94SO2NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O), SO2xe2x80x94 can be prepared as exemplified in Scheme 4. Appropiately substituted thioisocyanate is reacted with sodium azide to give the 5-thiotetrazole (J. Org. Chem. 1967, 32, 3580-3592). The thio-compound can be alkylated (J. Org. Chem. 1978, 43, 1197-1200) and then oxydized to the sulfoxide or sulfone. The thio-compound can also be converted to the sulfonyl chloride and the reacted with an amine to give the desired sulfonamide. The tetrazole compounds of this invention where Z is xe2x80x94Oxe2x80x94 can be prepared via the same method described in Scheme 4 by using appropiately substituted isocyanate as the startimg material. 
The tetrazole compounds of this invention where Z is xe2x80x94NHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94NHSO2xe2x80x94 can be prepared from 5-aminotetrazole, which can be prepared by Smiles Rearrangement as shown in Scheme 5. The thio-compound prepared as described in Scheme 4 is alkylated with 2-chloroacetamide. The resulting compound is then refluxed in ethanolic sodium hydroxide to give the corrresponding 5-amino-tetrazole (Chem. Pharm. Bull. 1991, 39, 3331-3334). The resulting 5-amino-tetrazole can then be alkylated or acylated to form the desired products. 
The N-linked imidazole ring M can be synthesized by the synthetic route shown in Scheme 6. Alkylation of Exe2x80x94Dxe2x80x94NH2 with 2-bromoethylacetate followed by reaction with Gold""s reagent in the presence of a base, such as NaOMe, or LDA, forms imidazole ring M. 
The general procedure to make C-linked imidazole ring M is described in Scheme 7. Aldehyde Exe2x80x94Dxe2x80x94CHO from Scheme 1 can be converted into cyano compound by treatment with hydroxyamine and then dehydration with POCl3. The amidine can be obtained from cyano compound by Pinner reaction, which can be cyclized with alpha-halo ester, ketone or aldehyde to form imidazole ring M. Alkylation or acylation of imidazole ring M for further modification as described in Scheme 1. 
As shown in Scheme 8, pyrazole ring M of the general Formula I such as those described in Scheme 1 can be prepared by the condensation of an appropriately substituted hydrazine with a variety of diketo esters. Condensations of this type typically afford a mixture of pyrazole regioisomers which can be effectively separated via silica gel column chromatography. Hydrolysis of the esters followed by coupling with an appropriate amine can afford the desired amide intermediate. Various substituents on the pyrazole N1 can then be manipulated to afford a variety of benzo, heterocyclic and bicylic compounds 
The above methodology when applied to diketo derivatives also affords a mixture of pyrazole regioisomers. These can be further manipulated to afford the compounds of Formula I as shown in Scheme 9. 
When ketoimidates are used for condensations with hydrazines the corresponding pyrazole amino esters regioadducts are obtained (Scheme 9). Conversion of these intermediates to the final compounds of formula I can then be accomplished by the protection of the amino functionality with a suitable protecting group commonly known to those in the art or by derivatization (such as a sulfonamide as in Scheme 10) then following the general synthetic strategy to prepare the compounds of this invention. 
The pyrazole ester intermediate can be further manipulated to the ketones by the cuprate methodology described by Knochel et. al (Scheme 11). Alternatively the ester can be reduced to either the alcohol or aldehyde via methods known to those in the art followed by either a reductive amination with an appropriate amine to an alkyl amine or by converting the alcohol to a leaving group which in turn can be displaced with a number of nucleophiles to provide the intermediates which on further manipulations should afford the compounds of this invention. 
Thio compounds such as those described in Scheme 12 can be easily prepared by the conversion of 5-hydroxy pyrazole to its thiol by treatment with Lawesson""s reagent in refluxing toluene. 
Compounds of this invention wherein the pyrazole ring M is replaced with a 1,2,3-triazole can be prepared as outlined in Scheme 13. 
The compounds of this invention where the ring M is 1,2,4-triazole can be easily obtained by the methodology of Huisgen et. al. (Liebigs Ann. Chem. 1962, 653, 105) by the cycloaddition of nitriliminium species (derived from the treatment of triethylamine and chloro hydrazone) and an appropriate nitrile dipolarophile as in Scheme 14. 
This methodology provides a wide variety of 1,2,4 triazoles with a varied substitution pattern at the 1,3 and 5 positions. Alternatively the 1,2,4 triazoles can also be prepared by the methodology of Zecchi et. al. (Synthesis 1986, 9, 772) via an aza Wittig condensation (Scheme 15). 
Alternatively the 1,2,4 triazoles can also be prepared via the methodology of Sauer et. al. (Tetr. Lett. 1968, 325) by the photolysis of a cyclic carbonate with an appropriate nitile (Scheme 16). 
For compounds of this invention the esters can be converted to the amide intermediates via the Weinreb methodology (Tetr. Lett. 1977, 48, 4171), i.e. the condensation of an appropriate amine aluminum complex with the ester (Scheme 17). 
Isoxazoline ring M of the general formula I wherein the 4 and 5 positions are substituted can be prepared following the 1,3-dipolar cycloaddition methodology outlined in Scheme 18. An appropriate benzhydroximinoyl chloride or heterocyclic oximinoylchloride or the oxime when subjected to the 1,3-dipolar cycloaddition protocol with a suitable 1,2-disubstituted olefin as a dipolarophile should afford a mixture of regioisomers. Separation of the regioisomers by column chromatography followed by the sequence of reactions as described previously should then afford the compounds of choice. Optically active isoxazolines can also be obtained by enzymatic resolution on the regioisomeric esters or by the use of an appropriate chiral auxilliary on the dipolarophile as described by Olsson et al (J. Org. Chem. 1988, 53, 2468). 
In the case of compounds with general formula I wherein the substrate in the cycloaddition process described in Scheme 18 utilizes an appropriately substituted crotonate ester. The crotonate esters can be obtained from commercial sources or can be obtained from ethyl-4-bromocrotonate by nucleophilic displacement reactions shown in Scheme 19. 
Trisubstituted olefins as dipolarophiles can be obtained from ethylpropiolate by the cuprate chemistry (Scheme 20) according to the method described by Deslongchamps et. al. (Synlett 1994, 660). 
Compounds of this invention with 1,3,4-triazole ring M can be easily obtained via the methodology of Moderhack et. al. (J. Prakt. Chem. 1996, 338, 169) as in Scheme 21. 
This reaction involves the condensation of a carbazide with an appropriately substituted commercially available thio isocyanate to the cyclic thiourea derivative as described previously. Alkylation or nucleophilic displacement reactions on the thiono intermediate then affords a thio alkyl or aryl intermediate which can be hydrolysed, oxidized and decarboxylated to the 5-H 2-thio triazole intermediate which can be effectively converted to the compounds of this invention. Alternatively the thiono urea intermediate can be oxidized directly to the 2-H triazole which can then be converted to the ester and then subjected to a variety of reactions shown above to obtain the compounds of this invention. The esters can also be converted to the amine via the Hoffmann rearrangement and this methodology provides a variety of analogs similar to those shown previously. The cyclic thiono urea intermediate can also be oxidized to the sulfonyl chloride by methods shown in early examples. This in turn can provide the sulfonamides shown in Scheme 22. 
Scheme 23 describes the general synthesis for pyrazoles which have thio and oxidized sulfur derivatives. An appropriately substituted amine is alkylated with ethyl bromoacetate and hydrolyzed to the glycine derivative. Preparation of the N-nitroso compound was easily achieved with sodium nitrite (J. Chem. Soc. 1935, 899). Cyclization to the syndone using acetic anhydride (J. Chem. Soc. 1935, 899) was following by the introduction of the sulfide unit using a sulfoxide as solvent and acetyl chloride as a activating reagent (Tetr. 1974, 30, 409). Photolytic cleavage of the sydnone in the presence of an acetylenic compound the 1,3,5 trisubstituted pyrazole as the major regioisomer (Chem. Ber. 1979, 112, 1206). These can be carried on, as described before, to the final compounds containing the sulfide, sulfoxide or sulfone functionality. 
Scheme 24 shows one possible synthesis of isoxazoles. Substituted benzaldehydes are reacted with hydroxyl amine then chlorinated to give the hydroximinoyl chloride according to the procedure of (J. Org. Chem. 1980, 45, 3916). Preparation of the nitrile oxide in situ with triethylamine and cycloaddition with a substituted alkyne gives a mixture of regioisomeric isoxazoles as shown by H. Kawakami (Chem. Lett. 1987, 1, 85). Preparation of the disubstituted alkyne is achieved by nucleophilic attack of the alkynyl anion on an electrophile as shown by Jungheim et al (J. Org. Chem. 1987, 57, 4007).
Alternatively, one could make the hydroxyiminoyl chloride of the R1a piece and react it with an appropriately substituted alkyne to give another set of regioisomeric isoxazoles which as separated chromatographically. 
An alternate procedure which produces only one regioisomer is described in Scheme 25. The methylated form of V can be deprotonated and silylated. Chlorination with carbon tetrachloride or fluorination with difluorodibromomethane under triethylborane catalysis give the geminal dihalo compound as shown by Sugimoto (Chem. Lett. 1991, 1319). Cuprate-mediated conjugate addition-elimination give the desired alkene as in Harding (J. Org. Chem. 1978, 43, 3874).
Alternatively, one can acylate with an acid chloride to form a ketone as in Andrews (Tetr. Lett. 1991, 7731) followed by diazomethane to form the enol ether. Each of these compounds can be reacted with a hydroximinoyl chloride in the presence of triethylamine to give one regioisomeric isoxazole as shown by Stevens (Tetr. Lett. 1984, 4587). 
When core substitutent R1a is CH2Q, the synthesis is shown in Scheme 26. After being treated with LDA, the ketone starting material reacts with PhSSO2Ph to give the phenylthiolated compound which reacts with hydrazine in acetic acid to form pyrazole derivative. The pyrazole ester reacts with an amine or aniline (previously treated with AlMe3) to provide amide. Oxidation of the sulfide with mCPBA gives the corresponding sulfone. Deprotonation of the sulfone with base, followed by trapping with an electrophile (Qxe2x80x94X) and treatment with SmI2 provided the desired compound after deprotection. 
Scheme 27 shows other methods of synthesis for R1axe2x95x90CH2Q or COQ. Protection of the hydroxyl group of hydroxyacetone with a benzyl halide and treatment with a base and CO(CO2Et)2 gives the tricarbonyl compound. Refluxing with NH2OMe.HCl in pyridine and ethanol in the presence of molecular sieve 3 xc3x85 gives the oxime. Cyclization of oxime with Exe2x80x94Dxe2x80x94NHNH2 provided pyrazole, which can be converted into the corresponding amide by reacting with an amine or aniline (previously activated with AlMe3). Debenzylation by catalytic hydrogenation provides the alcohol. The alcohol is converted into the tosylate with TsCl, followed by replacement with a nucleophile to provide the desired compound. The alcohol can also be oxidized to the corresponding aldehyde or acid, or further converted to ester or amide. 
Preparation of Compounds of Formula I with a Six-membered Heterocyclic Core
Scheme 28 describes the synthesis of compounds wherein M is a benzene ring and V is a nitro, protected sulfonamide or ester group and precursor of group Z of Formula I. The V group is placed on an appropriately substituted phenol either via nitration as shown by Poirier et al. (Tetrahedron 1989, 45(5), 1415), sulfonylation as shown by Kuznetsov (Akad. Nauk SSSR Ser. Khim 1990, 8, 1888) or carboxylation by Sartori et al. (Synthesis 1988, 10, 763). Bromination with triphenylphosphine and bromine (J. Am. Chem. Soc. 1964, 86, 964) gives the desired bromide. Suzuki coupling with the appropriate boronic acid provides the desired substituted pyridine. 
Scheme 29 thru 32 describe the synthesis of compounds wherein M is pyridine. Each scheme represents a different substitution pattern for the pyridine ring. In Scheme 29, a suitably protected aldehyde is subjected to base-catalyzed condensation with an activated ester to give after deprotection the desired aldehyde. Refluxing with ammonium chloride as shown by Dornow and Ische (Chem. Ber. 1956, 89, 876) provides the pyridinol which is brominated with POBr3 (Tjeenk et al. Rec. Trav. Chim. 1948, 67, 380) to give the desired 2-bromopyridine. Suzuki coupling with the appropriate boronic acid provides the desired substituted pyridine. 
Treatment of an appropriately substituted 5-ethoxyoxazole with an alkene as shown by Kondrat""eva et al. (Dokl. Akad. Nauk SSSR 1965, 164, 816) provides a pyridine with the V substituent at the para position. Bromination at the 3-position as shown by van der Does and Hertog (Rec. Trav. Khim. Pays-Bas 1965, 84, 951) followed by palladium-catalyzed boronic acid coupling provides the desired substituted pyridine. 
Scheme 31 describes a synthesis of a third substitution pattern on a pyridine ring. The appropriate tricarbonyl compound which can be prepared by methods described in Scheme 29 is treated with ammonium chloride to form the pyridinol which is subsequently brominated. Palladium-catalyzed coupling provides the desired substituted pyridine. 
Scheme 32 takes a suitably substituted dicarbonyl compound and by chemistry illustrated in Schemes 29 and 31, reacts it with ammonium chloride. Bromination gives the 3-bromopyridine which upon palladium-catalyzed coupling provides the desired substituted pyridine. 
Scheme 33 thru 35 describe the synthesis of compounds wherein M is pyridazine. Each scheme represents a different substitution pattern for the pyridazinering. In Scheme 33 an activated ester is reacted with an appropriately substituted xcex1-keto aldehyde and hydrazine as shown by Schmidt and Druey (Helv. Chim. Acta 1954, 37, 134 and 1467). Conversion of the pyridazinone to the bromide using POBr3 and palladium-catalyzed coupling provides the desired substituted pyridazine. 
In Scheme 34, glyoxal can react under basic conditions with an activated ketone and subsequently brominated/dehydro-brominated to give the desired ketoaldehyde. Alternatively, a protected ketone can react with an activated aldehyde, undergo bromination/dehydrobromination, be deprotected and oxidized to give the regioisomeric ketoaldehyde. Cyclization as shown by Sprio and Madonia (Ann. Chim. 1958, 48, 1316) with hydrazine followed by palladium-catalyzed coupling provides the desired substituted pyridazine. 
By analogy to Scheme 34, in Scheme 35 a aldehyde can be reacted with an activated ketone, brominated, dehydro-brominated and deprotected to give the desired diketone. Alternatively, a regioisomeric ketone can be placed through the same reaction sequence to produce an isomeric keto aldehyde. Reaction with hydrazine followed by palladium-catalyzed coupling provides the desired substituted pyridazine. 
Scheme 36 and 37 describe the synthesis of compounds wherein M is pyrimidine. Each scheme represents a different substitution pattern for the pyrimidine ring. In Scheme 36, a condensation with an appropriately substituted acid chloride and an activated ester followed by conjugate reduction by tin hydride (Moriya et al. J. Org. Chem. 1986, 51, 4708) gives the desired 1,4 dicarbonyl compound. Cyclization with formamidine or a substituted amidine followed by bromination gives the desired regioisomeric pyrimidine. Palladium-catalyzed coupling provides the desired substituted pyrimidine. 
Using similar chemistry, Scheme 37 shows how an amidine can be condensed with a 1,3-dicarbonyl compound and subsequently brominated in the 5-position (J. Het. Chem. 1973, 10, 153) to give a specific regioisomeric bromopyrimidine. Palladium-catalyzed coupling provides the desired substituted pyrimidine. 
Using the same ketoaldehyde from Scheme 37, cyclization with an appropriately substituted 1,2-diamine (Chimia 1967, 21, 510) followed by aromatization (Helv. Chim. Acta 1967, 50, 1754) provides a regioisomeric mixture of pyrazines as illustrated in Scheme 38. Bromination of the hydrobromide salt (U.S. Pat. No. 2,403,710) yields the intermediate for the palladium-catalyzed coupling step which occurs as shown above. 
Scheme 39 and 40 describe the synthesis of compounds wherein M is a 1,2,3-triazine. In Scheme 39, a vinyl bromide is palladium coupled to a molecule containing the substituent R1b. Allylic bromination followed by azide displacement provide the cyclization precursor. Triphenylphosphinemediated cyclization (J. Org. Chem. 1990, 55, 4724) give the 1-aminopyrazole which is subsequently brominated with N-bromosuccimide. Lead tetraacetate mediated rearrangement as shown by Neunhoeffer et al. (Ann. 1985, 1732) provides the desired regioisomeric 1,2,3-triazine. Palladium-catalyzed coupling provides the substituted triazine. 
In Scheme 40, an alkene is allylically brominated and the bromide is displaced to give a regioisomer of the azide in Scheme 39. Following the same reaction sequence as shown above, cyclization provides the 1-aminopyrazole. Bromination followed by lead tetraacetate mediated rearrangement give the 1,2,3-triazine. Palladium-catalyzed coupling provides the other desired triazine. 
Scheme 41 and 42 describe the synthesis of compounds wherein M is a 1,2,4-triazine. In Scheme 41, a nitrile is converted using hydrazine to give the amidrazone which is condensed with a xcex1-ketoester to give the triazinone as shown by Paudler and Lee (J. Org. Chem. 1971, 36, 3921). Bromination as shown by Rykowski and van der Plas (J. Org. Chem. 1987, 52, 71) followed by palladium-catalyzed coupling provides the desired 1,2,4-triazine. 
In Scheme 42, to achieve the opposite regioisomer the reaction scheme shown above is modify by the substituting a protected xcex1-ketoester. This allows the most nucleophilic nitrogen to attack the ester functionality setting up the opposite regiochemistry. Deprotection and thermal cyclization gives the triazinone which is brominated as shown above. Palladium-catalyzed coupling provides the other desired 1,2,4-triazine. 
Scheme 43 describes the synthesis of compounds wherein M is a 1,2,3,4-tetrazine. Lithiation of a vinyl bromide, transmetallation with tin, palladium catalyzed carbonylation and hydrazone formation provides a diene for a subsequent Diels-Alder reaction as shown by Carboni and Lindsey (J. Am. Chem. Soc. 1959, 81, 4342). Reaction with dibenzyl azodicarboxylate followed by catalytic hydrogenation to debenzylate and decarboxylate should give after bromination the desired 1,2,3,4-tetrazine. Palladium-catalyzed coupling provides the desired substitution. 
Preparation of Compounds of Formula I Containing a Bicyclic Core
Schemes 44 and 45 illustrate the preparation of benzopyrazole and indole core intermediates useful for synthesizing compounds of Formula I. The starting pyrazole N-oxide in Scheme 44 can be obtained by a method outlined in Chem. Ber. (1926) 35-359. The pyrazole N-oxide can be reduced by any number of methods including triphenylphosphine in refluxing toluene followed by the hydrolysis of the nitrile substituent to a carboxylic acid with base to give the benzopyrazole intermediate which may be coupled in the usual way to give a compound of Formula I. 
The starting indole in Scheme 45 may be obtained via the Fischer Indole Synthesis (Org. Syn, Col. Vol. III 725) from an appropriately substituted phenylhydrazine and acetophenone. Further elaboration using standard synthetic methods including the introduction of a 3-formyl group by treatment with POCl3 in DMF, the optional protection of the indole NH with the SEM group (TMSCH2CH2OCH2Cl, NaH, DMF) and oxidation of the aldehyde to a carboxylic acid which is now ready for transformation to compounds of Formula I. 
Preparation of Group Axe2x80x94B of Formula I
Compounds of this invention where B is either a carbocyclic or heterocyclic residue as defined in Formula 1 are coupled to A as shown generically and by specific example in Schemea 46 and 47, respectively. Either or both of A and B may be substituted with 0-2 R4. W is defined as a suitable protected nitrogen, such as NO2 or NHBOC; a protected sulfur, such as S-tBu or SMOM; or a methyl ester. Halogen-metal exchange of the bromine in bromo-B with n-butyl lithium, quenching with triisopropyl borate and acidic hydrolysis gives the required boronic acid, Bxe2x80x94B(OH)2. The Wxe2x80x94Axe2x80x94Br subunit may be already linked to ring M before the Suzuki coupling reaction. Deprotection provides the complete subunit. 
Scheme 47 describes a typical example of how the Axe2x80x94B subunit is prepared for attachment to ring M. 4-Bromoaniline is protected as Boc-derivative and the coupled to 2-(t-butylamino)sulfonylphenylboronic acid under Suzuki conditions. 2-(t-Butylamino)sulfonylphenylboronic acid is prepared by the method described by Rivero (Bioorg. Med. Chem. Lett. 1994, 189). Deprotection with TFA can provide the aminobiphen-4-yl compound. The aminobiphen-4-yl is then coupled to the core ring structures as described below. 
When B is defined as Xxe2x80x94Y, the following description applies. Groups A and B are available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practitioners skilled in the art of organic synthesis. The required reactive functional groups appended to analogs of A and B are also available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practitioners skilled in the art of synthesis. In the tables that follow the chemistry required to effect the coupling of A to B is outlined.
The chemistry of Table A can be carried out in aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from xe2x88x9220xc2x0 C. to the reflux point of the solvent and with or without a trialkylamine base.
The coupling chemistry of table B can be carried out by a variety of methods. The Grignard reagent required for Y is prepared from a halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0xc2x0 C. to the reflux point of the solvent. This Grignard reagent can reacted directly under very controlled conditions, that is low temperature (xe2x88x9220xc2x0 C. or lower) and with a large excess of acid chloride or with catalytic or stoichiometric copper bromide.dimethyl sulfide complex in dimethyl sulfide as a solvent or with a variant thereof. Other methods available include transforming the Grignard reagent to the cadmium reagent and coupling according to the procedure of Carson and Prout (Org. Syn. Col. Vol. 3 601, 1955) or coupling mediated by Fe(acac)3 according to Fiandanesse et al. (Tet. Lett., 4805, 1984), or a coupling mediated by manganese(II) catalysis (Cahiez and Laboue, Tet. Lett., 33(31), 4437, 1992).
The ether and thioether linkages of Table C can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at a temperature ranging from ambient to the reflux point of the solvent used.
The thioethers of Table C serve as a convenient starting material for the preparation of the sulfoxide and sulfone analogs of Table D. A combination of wet alumina and Oxone can provide a reliable reagents for the oxidation of the thioether to the sulfoxide as shown by Greenhalgh (Syn. Lett., 235, 1992). The sulfone can be prepared according to the method of Satoh (Chem. Lett., 381, 1992) using m-chloroperbenzoic acid.